Scientists Prevent Cerebral Palsy-like Brain Damage in Mice

Scientists at Washington University School of Medicine in St.
Louis have shown that a protein may help prevent the kind of brain
damage that occurs in babies with cerebral palsy.

Using a mouse model that mimics the devastating condition in
newborns, the researchers found that high levels of the protective
protein, Nmnat1, substantially reduce damage that develops when the
brain is deprived of oxygen and blood flow. The finding offers a
potential new strategy for treating cerebral palsy as well as
strokes, and perhaps Alzheimer's, Parkinson's and other
neurodegenerative diseases. The research is reported online in the
Proceedings of the National Academy of Sciences.

"Under normal circumstances, the brain can handle a temporary
disruption of either oxygen or blood flow during birth, but when
they occur together and for long enough, long-term disability and
death can result," says senior author David M. Holtzman, MD, the
Andrew and Gretchen Jones Professor and head of the Department of
Neurology. "If we can use drugs to trigger the same protective
pathway as Nmnat1, it may be possible to prevent brain damage that
occurs from these conditions as well as from neurodegenerative
diseases."

The researchers aren't exactly sure how Nmnat1 protects brain
cells, but they suspect that it blocks the effects of the powerful
neurotransmitter glutamate. Brain cells that are damaged or
oxygen-starved release glutamate, which can overstimulate and kill
neighboring nerve cells.

The protective effects of Nmnat1 were first identified five
years ago by Jeff Milbrandt, MD, PhD, the James S. McDonnell
Professor and head of genetics at Washington University, who showed
the protein can prevent damage to peripheral nerves in the body's
extremities. Phillip Verghese, PhD, a postdoctoral research
associate in Holtzman's laboratory, wanted to see if the protein's
protective effects extend to the brain.

"Cerebral palsy is sometimes attributable to brain injury that
stems from inadequate oxygen and blood flow to the brain before,
during or soon after birth," says first author Philip Verghese,
PhD, a postdoctoral research associate in Holtzman's laboratory.
"We wanted to see if those injuries still occur in the presence of
increased levels of Nmnat1."

The researchers evaluated the effects of oxygen and blood flow
deprivation in normal mice and in mice genetically engineered to
produce higher-than-normal levels of Nmnat1.

As early as six hours later, the mice with enhanced Nmnat1 had
markedly less injury to the brain.

A week later, when the researchers measured the amount of tissue
atrophy in the brain, they found that mice with high Nmnat1 had
experienced far less damage to key brain structures like the
hippocampus and cortex, which are known to be injured in cerebral
palsy.

In a series of follow-up studies with collaborators Jeff Neil,
MD, PhD, the Allen P. and Josephine B. Green Professor of
Neurology, and Yo Sasaki, PhD, research assistant professor of
genetics, the scientists were surprised at what they saw.

MRI scans of the brain showed that Nmnat1 might be even more
protective than the first experiment suggested. In mice with
boosted Nmnat1 levels, the scans revealed little to no brain
damage.

Laboratory studies of the brain cells indicated that Nmnat1
prevents a particular form of cell death.

"There are two types of injury in the developing brain from
inadequate oxygen and blood flow," Holtzman explains. "One is
necrosis, where cells swell rapidly, burst and die; another is
apoptosis, where the cells shrink and die. We found that Nmnat1
prevents necrosis."

Necrosis is believed to be responsible for killing brain cells
in ischemic stroke in adults, which temporarily cuts off oxygen and
blood flow to the brain. Dying cells flood the surrounding area
with a glutamate, which can harm nearby cells. When researchers
simulated this process in a test tube, fewer brain cells died in
the presence of high Nmnat1.

Scientists in Milbrandt's and Holtzman's laboratories are
following up on several potential explanations for Nmnat1's
protective effects. Holtzman plans to test the protein in other
models of brain injuries and neurodegenerative diseases.